The long-term objective of this research program is to understand the projection of the vestibular efferent neurons to the vestibular periphery in the context of the fundamental molecular sensory organization of the receptors and the vestibular primary afferents. To accomplish this it is necessary to understand the distribution of the efferent intracellular pathways in the vestibular epithelia. One approach towards this goal is to determine the distribution of the effects of efferent transmitters on cytoplasmic signaling molecules (second messengers) regulating synaptic events. Opioid peptides are putative efferent neurotransmitters and have demonstrated modulatory effects on the vestibular afferent discharge. Opioid peptides act through G protein coupled receptors on adenylyl cyclases, which catalyze the synthesis of the second messenger cAMP. Opioid receptor activation-induced increase or decrease in levels of cAMP results in stimulatory or inhibitory effects on the afferent neurons. This application seeks funding to address two questions: 1) What are the cAMP mediated opioid signal transduction pathways in the vestibular epithelia and how are they distributed (center vs. periphery) in the vestibular epithelia? and 2) What are the topographic distributions of one class of receptors, the f opioid receptors, in the rat vestibular end organs? Specific Aim I will determine the effects of mu opioid receptor activation on cAMP in the vestibular epithelia of rats (Rattus norvegicus), the G proteins involved and the location of the effects in the epithelia. Specific Aim II will determine the distributions of mu opioid receptors and of isoforms of adenylyl cyclase immunoreactivity in the vestibular epithelia of rats. These data are essential for the interpretation of future experiments that will explore the role of these receptor's vestibular efferent/afferent interactions. After a detailed molecular understanding of this efferent/afferent interaction, experimental studies can be performed to induce changes in this system and to study the effects of these changes, thereby elucidating the contribution and importance of each of its component. These studies will provide a model for determining the role of the efferent and afferent pathways during vestibular compensation, after vestibular injury, or during specific vestibular disorders such as Meniere's disease or motion sickness. In addition, characterization distributions of the neurotransmitter pathways and of their molecular organization may lead to advances in the pharmacotherapy of patients with vestibular dysfunction.